EP2697233B1 - Composés de triazine macrocycliques pour le traitement de l'hépatite c - Google Patents

Composés de triazine macrocycliques pour le traitement de l'hépatite c Download PDF

Info

Publication number
EP2697233B1
EP2697233B1 EP12715793.1A EP12715793A EP2697233B1 EP 2697233 B1 EP2697233 B1 EP 2697233B1 EP 12715793 A EP12715793 A EP 12715793A EP 2697233 B1 EP2697233 B1 EP 2697233B1
Authority
EP
European Patent Office
Prior art keywords
hcv
compound
inhibitors
pharmaceutically acceptable
acceptable salt
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Not-in-force
Application number
EP12715793.1A
Other languages
German (de)
English (en)
Other versions
EP2697233A1 (fr
Inventor
Tao Wang
Li-Qiang Sun
Paul Michael Scola
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Bristol Myers Squibb Co
Original Assignee
Bristol Myers Squibb Co
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Bristol Myers Squibb Co filed Critical Bristol Myers Squibb Co
Publication of EP2697233A1 publication Critical patent/EP2697233A1/fr
Application granted granted Critical
Publication of EP2697233B1 publication Critical patent/EP2697233B1/fr
Not-in-force legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
    • C07D487/16—Peri-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
    • C07D487/18—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/16—Peri-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/18—Bridged systems

Definitions

  • the disclosure generally relates to the novel compounds of formula I including pharmaceutically acceptable salts, which have activity against hepatitis C virus (HCV) and are useful in treating those infected with HCV.
  • HCV hepatitis C virus
  • the disclosure also relates to compositions and methods of using these compounds.
  • HCV Hepatitis C virus
  • genotypes of HCV differ in their worldwide distribution, and the clinical significance of the genetic heterogeneity of HCV remains elusive despite numerous studies of the possible effect of genotypes on pathogenesis and therapy.
  • HCV is a member of the Flaviviridae family of viruses with a single-stranded positive-sense RNA genome. Following infection of host cells, the 9.6 Kb genome is translated into a polyprotein precursor of approximately 3,000 amino acids (reviewed in Lindenbach, B. D. and Rice, C. M. Nature. 2005, 436:933-938 ; Moradpour, D, Penin, F., and Rice, C. M. Nature Reviews. 2007, 5:453-463 ). Post-translational processing by both cellular and viral proteases results in the generation of at least 10 separate viral proteins. The structural proteins (which by definition are found in mature virions) include core, E1, E2, and possibly p7, and originate from the amino-terminal region of the polyprotein.
  • the core protein assembles into the viral nucleocapsid.
  • the E1 and E2 glycoproteins form heterodimers that are found within the lipid envelope surrounding the viral particles, and mediate host cell receptor binding and entry of the virus into cells.
  • p7 is a structural protein, and its role in replication has yet to be defined. However p7 is believed to form an ion channel in cellular membranes, preventing acidification of intracellular compartments in which virions are assembled, and it has been shown to be essential for viral replication and assembly.
  • the nonstructural proteins NS2, NS3, NS4A, NS4B, NS5A, and NS5B are produced through maturational cleavages of the carboxy-terminal region of the polyprotein.
  • NS2 along with the amino terminus of NS3 form the NS2-3 metalloprotease which cleaves at the NS2-NS3 junction. Additionally, NS2 is involved in assembly and egress of nascent virions.
  • the NS3 protein contains both a serine protease in its amino-terminal region, and a nucleotide-dependent RNA helicase in its carboxy-terminal region.
  • NS3 forms a heterodimer with the NS4A protein, constituting the active protease which mediates cleavages of the polyprotein downstream of NS3, both in cis, at the NS3-NS4A cleavage site, and in trans, for the remaining NS4A-NS4B, NS4B-NS5A, NS5A-NS5B sites.
  • the complex formation of the NS3 protein with NS4A seems necessary to the processing events, enhancing the proteolytic efficiency at all of the sites.
  • the NS3 protein also exhibits nucleoside triphosphatase and RNA helicase activities.
  • the NS4B protein has been shown to be important for localization of HCV proteins into replication complexes in altered membranous structures within the cell.
  • NS5B encodes an RNA-dependent RNA polymerase that is involved in the replication of HCV.
  • HCV replicons containing the untranslated regions 5' and 3' to the coding sequence fused to the nonstructural proteins or the full-length polyprotein, are competent for translation, viral protein expression, and replication within cultured cells ( Lohmann, V. et al. Science. 1999, 285:110-113 ; Moradpour, D, Penin, F., and Rice, C. M. Nature Reviews. 2007, 5:453-463 ).
  • the replicon system has proven valuable for the identification of inhibitors targeting the nonstructural proteins associated with these functions.
  • only limited subsets of HCV genotypes have been used to generate functional replicons.
  • Hsu, M. et al. Proc. Natl. Acad. Sci. USA. 2003, 100:7271-7276 These systems yield HCV pseudoparticles that bind to and enter host cells in a manner which is believed to be analogous to the natural virus, thus making them a convenient tool to study the viral entry steps as well as to identify inhibitors block this process.
  • the infectious virus is useful for studying the complete HCV replication cycle, including identifying inhibitors of not only the replication proteins, but those involved in early steps in virus infection (entry and uncoating) and production of progeny viruses (genome packaging, nucleocapsid assembly, virion envelopment and egress).
  • Triazines have been disclosed. See WO 2009/091388 and US 2009/0286778 .
  • the invention provides technical advantages, for example, the compounds are novel and are effective against hepatitis C. Additionally, the compounds provide advantages for pharmaceutical uses, for example, with regard to one or more of their mechanism of action, binding, inhibition efficacy, target selectivity, solubility, safety profiles, or bioavailability.
  • One aspect of the invention is a compound of formula I where
  • R 1 is haloalkyl
  • R 2 is hydrogen
  • R 3 is hydrogen
  • R 4 is hydrogen
  • Ar 1 is pyridindiyl, pyrimidindiyl, or pyrazoldiyl
  • X is O or NR 2
  • Y is an alkylene or alkenylene chain containing 0-6 groups selected from the group consisting of O, NR 3 , C(O), C(O)O, C(O)NR 4 , OC(O)NR 4 , NR 4 C(O)NR 4 , NR 4 C(NR 12 )NR 4 , and Z, provided that O, NR 3 , C(O), C(O)O, C(O)NR 4 , OC(O)NR 4 , NR 4 C(O)NR 4 , and NR 4 C(NR 12 )NR 4 do not directly bond to each other, such that ring A is 14-36 membered; and where the alkylene or alkenylene
  • Another aspect of the invention is a compound of formula I where R 1 is haloalkyl.
  • Another aspect of the invention is a compound of formula I where R 1 is trifluoroethyl.
  • Another aspect of the invention is a compound of formula I where Ar 1 is pyridindiyl, pyrimidindiyl, or pyrazoldiyl.
  • Another aspect of the invention is a compound of formula I where Ar 1 is pyridindiyl.
  • Another aspect of the invention is a compound of formula I where Ar 1 is pyrimidindiyl.
  • Another aspect of the invention is a compound of formula I where Ar 1 is pyrazoldiyl.
  • Another aspect of the invention is a compound of formula I where X is O.
  • Another aspect of the invention is a compound of formula I where X is NR 2 .
  • Another aspect of the invention is a compound of formula I where Y is an alkylene or alkenylene chain containing 0-6 groups selected from the group consisting of O, NR 3 , C(O), C(O)O, C(O)NR 4 , OC(O)NR 4 , NR 4 C(O)NR 4 , NR 4 C(NR 12 )NR 4 , and Z, provided that O, NR 3 , C(O), C(O)O, C(O)NR 4 , OC(O)NR 4 , NR 4 C(O)NR 4 , and NR 4 C(NR 12 )NR 4 do not directly bond to each other, such that ring A is 14-36 membered; and where the alkylene or alkenylene chain is substituted with 0-6 alkyl substituents.
  • any scope of any variable including R 1 , R 2 , R 3 , R 4 , Ar 1 , X, Y, and Z, can be used independently with the scope of any other instance of a variable.
  • Alkyl means a straight or branched alkyl group composed of 1 to 6 carbons.
  • Alkenyl means a straight or branched alkyl group composed of 2 to 6 carbons with at least one double bond.
  • Cycloalkyl means a monocyclic ring system composed of 3 to 7 carbons.
  • Alkylene means a straight or branched divalent alkyl group composed of 2 to 36 carbons.
  • Alkenylene means a straight or branched divalent alkyl group composed of 2 to 36 carbons with at least one double bond.
  • Y is an alkylene or alkenylene chain with sufficient carbons and optionally other defined groups to form a 13-36 membered ring.
  • Cycloalkylene means a divalent cycloalkane moiety composed of 3 to 7 carbons and includes gem-divalency (for example 1,1-cyclopropanediyl) as well as non-gem-divalency (for example, 1,4-cyclohexanediyl).
  • Alkylidinyl means a divalent alkene substituent where the divalency occurs on the same carbon of the alkene.
  • Haldroxyalkyl means straight and branched isomers composed of 1 to 6 carbon atoms for the alkyl moiety.
  • Halo means fluor, chloro, bromo, or iodo.
  • Haloalkyl and “haloalkoxy” include all halogenated isomers from monohalo substituted alkyl to perhalo substituted alkyl.
  • Aryl includes carbocyclic and heterocyclic aromatic substituents. Phenylene is a divalent benzene ring.
  • Ar 1 is a divalent heteroaryl ring with respect to forming ring A as in formula I. Parenthetic and multiparenthetic terms are intended to clarify bonding relationships to those skilled in the art. For example, a term such as ((R)alkyl) means an alkyl substituent further substituted with the substituent R.
  • the invention includes all pharmaceutically acceptable salt forms of the compounds.
  • Pharmaceutically acceptable salts are those in which the counter ions do not contribute significantly to the physiological activity or toxicity of the compounds and as such function as pharmacological equivalents. These salts can be made according to common organic techniques employing commercially available reagents. Some anionic salt forms include acetate, acistrate, besylate, bromide, camsylate, chloride, citrate, fumarate, glucouronate, hydrobromide, hydrochloride, hydroiodide, iodide, lactate, maleate, mesylate, nitrate, pamoate, phosphate, succinate, sulfate, tartrate, tosylate, and xinofoate.
  • Some cationic salt forms include ammonium, aluminum, benzathine, bismuth, calcium, choline, diethylamine, diethanolamine, lithium, magnesium, meglumine, 4-phenylcyclohexylamine, piperazine, potassium, sodium, tromethamine, and zinc.
  • the invention includes all stereoisomeric forms, including enantiomers and diastereomers as well as mixtures of stereoisomers such as racemates. Some stereoisomers can be made using methods known in the art. Stereoisomeric mixtures of the compounds and related intermediates can be separated into individual isomers according to methods commonly known in the art. The use of wedges or hashes in the depictions of molecular structures in the following schemes and tables is intended only to indicate relative stereochemistry, and should not be interpreted as implying absolute stereochemical assignments.
  • the invention is intended to include all isotopes of atoms occurring in the present compounds.
  • Isotopes include those atoms having the same atomic number but different mass numbers.
  • isotopes of hydrogen include deuterium and tritium.
  • Isotopes of carbon include 13 C and 14 C.
  • Isotopically-labeled compounds of the invention can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described herein, using an appropriate isotopically-labeled reagent in place of the non-labeled reagent otherwise employed. Such compounds may have a variety of potential uses, for example as standards and reagents in determining biological activity. In the case of stable isotopes, such compounds may have the potential to favorably modify biological, pharmacological, or pharmacokinetic properties.
  • HCV pseudoparticles produced using standardized methodology ( Bartosch, B., Dubuisson, J. and Cosset, F.-L. J. Exp. Med. 2003, 197:633-642 ) were made via a liposome-based transfection procedure of 293T cells with plasmids expressing the murine leukemia virus capsid and polymerase proteins, an MLV genome encoding the luciferase reporter gene, and envelope glycoproteins from either HCV or vesicular stomatitis virus (VSV).
  • the genotype 1a HCV E1 and E2 envelope coding sequences were derived from the H77C isolate (GenBank accession number AF009606).
  • Media containing pseudoparticles was collected 3 days following transfection, filtered, and stored at -20°C as a viral stock. Infections were performed in 384-well plates by mixing pseudovirus with 1 x 10 4 Huh7 cells/well in the presence or absence of test inhibitors, followed by incubation at 37°C. Luciferase activity, reflecting the degree of entry of the pseudoparticles into host cells, was measured 2 days after infection. The specificity of the compounds for inhibiting HCV was determined by evaluating inhibition of VSV pseudoparticle infection.
  • Test compounds were serially diluted 3-fold in dimethyl sulfoxide (DMSO) to give a final concentration range in the assay of 50.0 ⁇ M to 0.04 pM.
  • Maximum activity (100% of control) and background were derived from control wells containing DMSO but no inhibitor or from uninfected wells, respectively.
  • the individual signals in each of the compound test wells were then divided by the averaged control values after background subtraction and multiplied by 100% to determine percent activity.
  • Assays were performed in duplicate and average EC 50 values (reflecting the concentration at which 50% inhibition of virus replication was achieved) were calculated.
  • Activity Range EC 50 (nM) 1002 B 2090.00 1004 C 1006 C 1008 B 1009 C 8178.00 1012 C 1013 1014 B 1016 B 1017 1018 1019 C 1021 A 1022 C 1023 C 1024 B 1025 B 1027 C 1028 A 205.10 1030 C 1031 C 1032 A 1033 C 1035 C 1036 B 1037 B 1038 B 1039 C 1040 B 2001 2002 A 2003 2005 2006 A 2007 A 105.40 3001 A 3002 A 134.00
  • compositions comprising a compound, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • compositions further comprising a compound having anti-HCV activity.
  • Another aspect of the invention is a composition where the compound having anti-HCV activity is an interferon.
  • the interferon is selected from interferon alpha 2B, pegylated interferon alpha, consensus interferon, interferon alpha 2A, and lymphoblastoid interferon tau.
  • compositions where the compound having anti-HCV activity is a cyclosporin.
  • cyclosporin is cyclosporin A.
  • compositions where the compound having anti-HCV activity is selected from the group consisting of interleukin 2, interleukin 6, interleukin 12, a compound that enhances the development of a type 1 helper T cell response, interfering RNA, anti-sense RNA, Imiqimod, ribavirin, an inosine 5'-monophospate dehydrogenase inhibitor, amantadine, and rimantadine.
  • Another aspect of the invention is a composition where the compound having anti-HCV activity is effective to inhibit the function of a target selected from HCV metalloprotease, HCV serine protease, HCV polymerase, HCV helicase, HCV NS4B protein, HCV entry, HCV assembly, HCV egress, HCV NS5A protein, IMPDH, and a nucleoside analog for the treatment of an HCV infection.
  • a target selected from HCV metalloprotease, HCV serine protease, HCV polymerase, HCV helicase, HCV NS4B protein, HCV entry, HCV assembly, HCV egress, HCV NS5A protein, IMPDH, and a nucleoside analog for the treatment of an HCV infection.
  • compositions comprising a compound, or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable carrier, an interferon and ribavirin.
  • Also disclosed is a method of inhibiting the function of the HCV replicon comprising contacting the HCV replicon with a compound or a pharmaceutically acceptable salt thereof.
  • Also disclosed is a method of inhibiting the function of the HCV NS5B protein comprising contacting the HCV NS5B protein with a compound or a pharmaceutically acceptable salt thereof.
  • Also disclosed is a method of treating an HCV infection in a patient comprising administering to the patient a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof.
  • the compound is effective to inhibit the function of the HCV replicon.
  • the compound is effective to inhibit the function of the HCV NS5B protein.
  • Also disclosed is a method of treating an HCV infection in a patient comprising administering to the patient a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, in conjunction with (prior to, after, or concurrently) another compound having anti-HCV activity.
  • interferon is selected from interferon alpha 2B, pegylated interferon alpha, consensus interferon, interferon alpha 2A, and lymphoblastoid interferon tau.
  • the other compound having anti-HCV activity is a cyclosporin.
  • cyclosporin is cyclosporin A.
  • the other compound having anti-HCV activity is selected from interleukin 2, interleukin 6, interleukin 12, a compound that enhances the development of a type 1 helper T cell response, interfering RNA, anti-sense RNA, Imiqimod, ribavirin, an inosine 5'-monophospate dehydrogenase inhibitor, amantadine, and rimantadine.
  • the other compound having anti-HCV activity is effective to inhibit the function of a target selected from the group consisting of HCV metalloprotease, HCV serine protease, HCV polymerase, HCV helicase, HCV NS4B protein, HCV entry, HCV assembly, HCV egress, HCV NS5A protein, IMPDH, and a nucleoside analog for the treatment of an HCV infection.
  • a target selected from the group consisting of HCV metalloprotease, HCV serine protease, HCV polymerase, HCV helicase, HCV NS4B protein, HCV entry, HCV assembly, HCV egress, HCV NS5A protein, IMPDH, and a nucleoside analog for the treatment of an HCV infection.
  • “Therapeutically effective” means the amount of agent required to provide a meaningful patient benefit as understood by practitioners in the field of hepatitis and HCV infection.
  • Patient means a person infected with the HCV virus and suitable for therapy as understood by practitioners in the field of hepatitis and HCV infection.
  • compositions comprised of a therapeutically effective amount of a compound or its pharmaceutically acceptable salt and a pharmaceutically acceptable carrier and may contain conventional excipients.
  • Pharmaceutically acceptable carriers are those conventionally known carriers having acceptable safety profiles.
  • Compositions encompass all common solid and liquid forms including for example capsules, tablets, losenges, and powders as well as liquid suspensions, syrups, elixers, and solutions.
  • Compositions are made using common formulation techniques, and conventional excipients (such as binding and wetting agents) and vehicles (such as water and alcohols) are generally used for compositions. See, for example, Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, PA, 17th edition, 1985 .
  • compositions are normally formulated in dosage units and compositions providing from about 1 to 1000 mg of the active ingredient per dose are preferred. Some examples of dosages are 1 mg, 10 mg, 100 mg, 250 mg, 500 mg, and 1000 mg. Generally, other agents will be present in a unit range similar to agents of that class used clinically. Typically, this is 0.25-1000 mg/unit.
  • Liquid compositions are usually in dosage unit ranges. Generally, the liquid composition will be in a unit dosage range of 1-100 mg/mL. Some examples of dosages are 1 mg/mL, 10 mg/mL, 25 mg/mL, 50 mg/mL, and 100 mg/mL. Generally, other agents will be present in a unit range similar to agents of that class used clinically. Typically, this is 1-100 mg/mL.
  • the invention encompasses all conventional modes of administration; oral and parenteral methods are preferred.
  • the dosing regimen will be similar to other agents used clinically.
  • the daily dose will be 1-100 mg/kg body weight daily.
  • more compound is required orally and less parenterally.
  • the specific dosing regime will be determined by a physician using sound medical judgement.
  • the invention also encompasses methods where the compound is given in combination therapy. That is, the compound can be used in conjunction with, but separately from, other agents useful in treating hepatitis and HCV infection.
  • the compound will generally be given in a daily dose of 1-100 mg/kg body weight daily in conjunction with other agents.
  • the other agents generally will be given in the amounts used therapeutically.
  • the specific dosing regime will be determined by a physician using sound medical judgement.
  • Table 2 Some examples of compounds suitable for compositions and methods are listed in Table 2.
  • the compounds may be made by methods known in the art including those described below and including variations within the skill of the art. Some reagents and intermediates are known in the art. Other reagents and intermediates can be made by methods known in the art using readily available materials.
  • the variables (e.g. numbered "R" substituents) used to describe the synthesis of the compounds are intended only to illustrate how to make the compounds and are not to be confused with variables used in the claims or in other sections of the specification. The following methods are for illustrative purposes and are not intended to limit the scope of the invention.
  • iPr 2 NEt (1.83 mL) was added to each of these suspensions.
  • Suspensions were applied to 6-ml silica SPE cartridges, eluting w/ 4 mls MeOH each, collecting into 16x100 mm culture tubes. Samples were blown down in the Zymark tabletop dryer at 40° C for 3 hours. 1 mL DMF was added to each vial. Contents were transferred to 96 well 25 ⁇ m filter plate collecting into a 96 well deep-well plate. Vials was rinsed and transferred to the appropriate wells of the filter plate. 30 ⁇ L of contents was removed from each well and diluted to 1000 ⁇ Ls for LC/MS analysis. The mixtures were purified by preparative HPLC.
  • WFD-UPLC-002 ACN (2x50mm, 1.7um, 5min): Time B% Flow Time B% Flow _0.00' _0 _0.83 _5.50' _0 _0.83 _4.00' 100 _0.83 _5.00' 100 _0.83 _5.10' _0 _0.83
  • WFD-MUX-004 (4.6x50mm): Time B% Flow Time B% Flow _0.00' _0 _2.0 10.00' _0 _2.0 _8.00' 100 _2.0 _9.00' 100 _2.0 _9.10' 100 _2.0 Compd # HPLC Rt Obs.
  • Step 1 To a solution of 2,4-dichloro-6-(2,2,2-trifluoroethoxy)-1,3,5-triazine (0.496 g, 2 mmol) and Hunig'sBase (0.699 mL, 4.00 mmol) in THF (8 mL) was added 1H-pyrazol-3-amine (0.174 g, 2.100 mmol) and stirred for 16 h. The solution will be used in the next step as it is. To the above solution was added Hunig'sBase (699 ⁇ l, 4.00 mmol) followed by 4-(aminomethyl)phenol (246 mg, 2.000 mmol) and stirred for 16 h. Concentration and purification by Biotage eluting with 2.5%-5% MeOH in CH 2 Cl 2 gave 600 mg of the desired product as a solid. MS m/z (M+H) + 382.08.
  • Step 2 To a solution of 4-((4-(1H-pyrazol-3-ylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)methyl)phenol (66 mg, 0.173 mmol) and 1,2-bis(2-iodoethoxy)ethane (64.0 mg, 0.173 mmol) in DMF (10 mL) was added Cs 2 CO 3 (226 mg, 0.692 mmol). The resulting mixture was stirred at rt for 16 hrs. DMF was removed under vacuum. The residue was purified by prep HPLC to give 5 mg of the desired product compound 2001 as a solid. MS m/z (M+H) + 496.01.
  • Step 1 To slurry of 5-amino-1H-pyrazole-3-carboxylic acid (0.318 g, 2.5 mmol), tert-butyl 3-aminopropylcarbamate (0.479 g, 2.75 mmol) and Hunig'sBase (2.183 mL, 12.50 mmol) in CH 2 Cl 2 (8 mL) was added PyBOP (1.561 g, 3.00 mmol) and thr resulting solution was stirred for 16 h. After concentration, the residue was purified by Biotage eluting with 5%-20% MeOH in CH 2 Cl 2 to give 700 mg of a crude product that will be used as it is in the next step. MS m/z (M+H) + 284.10.
  • Step 2 To a solution of 2,4-dichloro-6-(2,2,2-trifluoroethoxy)-1,3,5-triazine (0.620 g, 2.5 mmol) and Hunig'sBase (1.747 mL, 10.00 mmol) in THF (8 mL) was added tert-butyl 3-(5-amino-1H-pyrazole-3-carboxamido)propylcarbamate (0.708 g, 2.500 mmol) and stirred for 16 h. To the above solution was added Hunig'sBase (873 ⁇ l, 5.00 mmol) followed by 4-(aminomethyl)phenol (308 mg, 2.500 mmol) and stirred for 16 h. Concentration and purification by Biotage eluting with 2.5%-5% MeOH in CH 2 Cl 2 gave 700 mg of the desired product as a solid. MS m/z (M+H) + 582.12.
  • Step 3 A solution of tert-butyl 3-(5-(4-(4-hydroxybenzylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)-1H-pyrazole-3-carboxamido)propylcarbamate (116 mg, 0.2 mmol) in TFA (1ml, 12.98 mmol) was stirred for 4h. TFA was removed under vacuum. The residue wiil be used in the next step as it is. MS m/z (M+H) + 481.99.
  • Step 4 To a solution of N-(3-aminopropyl)-5-(4-(4-hydroxybenzylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)-1H-pyrazole-3-carboxamide, 2 HCl (111 mg, 0.2 mmol) and 1,4-diiodobutane (62.0 mg, 0.200 mmol) in DMF (20 mL) was added Cs 2 CO 3 (261 mg, 0.800 mmol). The resulting mixture was stirred at rt for 16 hrs. DMF was removed under vacuum. The residue was purified by prep HPLC to give 50 mg starting material, 2 mg of compound 2003 Compound 2003: MS m/z (M+H) + 536.06;
  • Step 1 To a solution of 2,4-dichloro-6-(2,2,2-trifluoroethoxy)-1,3,5-triazine (0.496 g, 2 mmol) and Hunig'sBase (0.699 mL, 4.00 mmol) in THF (8 mL) was added methyl 2-(4-amino-1H-pyrazol-1-yl)acetate (0.326 g, 2.100 mmol) and stirred for 16 h. The solution will be used in the next step as it is. To the above solution was added Hunig'sBase (699 ⁇ l, 4.00 mmol) followed by 4-(aminomethyl)phenol (246 mg, 2.000 mmol) and stirred for 16 h. After concentration, the solid was collected washing with CH 2 Cl 2 to give 700 mg of the desired product as a solid. MS m/z (M+H) + 453.97.
  • Step 2 To a solution of methyl 2-(4-(4-(4-hydroxybenzylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)-1H-pyrazol-1-yl)acetate (91 mg, 0.2 mmol) and tert-butyl 4-bromobutylcarbamate (50.4 mg, 0.200 mmol) in DMF (1 mL) was added Cs 2 CO 3 (261 mg, 0.800 mmol). The resulting mixture was stirred at 60°C for 0.5h in microwave. DMF was removed under vacuum. The residue was purified by prep HPLC to give 22 mg of the desired product. MS m/z (M+H) + 611.03.
  • Step 3 A solution of 2-(4-(4-(4-(4-(4-(tert-butoxycarbonylamino)butoxy)benzylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)-1H-pyrazol-1-yl)acetic acid (45 mg, 0.074 mmol) and 4 M hydrogen chloride in dioxane (1 ml, 4.00 mmol) was stirred for 4h. The solvent was removed under vacuum. The residue wiil be used in the next step as it is. MS m/z (M+H) + 510.96.
  • Step 4 To slurry of 2-(4-(4-(4-(4-(4-aminobutoxy)benzylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)-1H-pyrazol-1-yl)acetic acid, 2 HCl (21.00 mg, 0.036 mmol) and Hunig'sBase (0.031 mL, 0.180 mmol) in CH2Cl2 (Volume: 8 mL) was added PyBOP (28.1 mg, 0.054 mmol) and thr resulting solution was stirred for 16 h. After concentration, the residue was purified by prep HPLC to give 5 mg of the desired product as a solid. MS m/z (M+H) + 492.96.
  • Step 1 To a solution of tert-butyl 2-(4-nitro-1H-pyrazol-1-yl)ethylcarbamate (1.7 g, 6.63 mmol) in EtOH (Volume: 30 mL) was added 5% Pt(S) on carbon (340 mg, 0.087 mmol) and the suspesion was hydrogenated at 50 PSI for 16 h. After filtration through a DClite plug washing with ethyl acetate, filtrate was concentrated, purified by Biotage eluting with 5% MeOH in CH2Cl2 to give 580 mg of desired product. MS m/z (M+Na) + 249.09.
  • Step 2 To a solution oftert-butyl 2-(4-amino-1H-pyrazol-1-yl)ethylcarbamate (0.566 g, 2.500 mmol) and Hunig'sBase (0.873 mL, 5.00 mmol) in THF (8 mL) was added tert-butyl 2-(4-amino-1H-pyrazol-1-yl)ethylcarbamate (0.566 g, 2.500 mmol) and stirred for 16 h. The solution will be used in the next step as it is.
  • Step 3 To a solution of tert-butyl 2-(4-(4-(4-hydroxybenzylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)-1H-pyrazol-1-yl)ethylcarbamate (105 mg, 0.2 mmol), 3-bromopropan-1-ol (38.9 mg, 0.280 mmol), and PPh 3 (84 mg, 0.320 mmol) in THF (2 mL) at 0°C was added DEAD (0.062 mL, 0.320 mmol). The resulting solution was srtirred for 16h at rt. After concentration, purification by Biotage eluting with 50% ethyl acetate in hexane to give 25 mg of the desired product as an oil. MS m/z (M+H) + 646.91.
  • Step 4 To a solution of tert-butyl 2-(4-(4-(4-(3-bromopropoxy)benzylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)-1H-pyrazol-1-yl)ethylcarbamate (10 mg, 0.015 mmol) in CH2Cl2 (1 mL) was added TFA (0.2 ⁇ l, 2.60 ⁇ mol). The resulting solution was stirred for 1 h. The solvents were removed and the residue was used as it was without any further purification.MS m/z (M+H) + 546.86.
  • Step 5 To a solution of N2-(1-(2-aminoethyl)-1H-pyrazol-4-yl)-N4-(4-(3-bromopropoxy)benzyl)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazine-2,4-diamine (5 mg, 9.17 ⁇ mol) in 7 mL microwave vial in MeCN (2 mL) was added K 2 CO 3 (1.267 mg, 9.17 ⁇ mol). The resulting mixture was stirred in microwave at 120°C for 1 h. The solvents were removed and the residuewas was purified by prep HPLC to give 3.4 mg of the product as TFA salt. MS m/z (M+H) + 645.00.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Virology (AREA)
  • Molecular Biology (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Claims (12)

  1. Composé de la formule I :
    Figure imgb0015
     dans laquelle
    R1 est alkyle, hydroxyalkyle, alkoxyalkyle, halogénoalkyle, cycloalkyle, hydroxycycloalkyle, alkoxycycloalkyle, halogénocycloalkyle, cycloalcényle, benzyle, indanyle ou alkylcarbonyle; :
    R2 est hydrogène, alkyle, alkylcarbonyle, alkoxycarbonyle, aminocarbonyle, alkylaminocarbonyle, ou dialkylaminocarbonyle;
    R3 est hydrogène, alkyle, alkylcarbonyle, alkoxycarbonyle, aminocarbonyle, alkylaminocarbonyle, ou dialkylaminocarbonyle;
    R4 est hydrogène ou alkyle;
    Ar1 est pyridindyile, pyrimidindyile, pyrazindyile, pyridazindyile, pyrazoldyile, ou imidazoldiyle ;
    X est O ou NR2 ;
    Y est une chaîne alcylène ou alcénylène contenant de 0 à 6 groupes sélectionnés dans le groupe constitué de O, NR3, C(O), C(O)O, C(O)NR4, OC(O)NR4, NR4C(O)NR4, NR4C(NR12)NR4, et Z, à condition que O, NR3, C(O), C(O)O, C(O)NR4, OC(O)NR4, NR4C(O)NR4, et NR4C(NR12)NR4 ne se lient pas directement l'un à l'autre, de sorte que le noyau A comprend de 14 à 36 éléments ; et où la chaîne alcylène ou alcénylène est substituée par 0 à 6 substituants alkyle ; et
    Z est C3-7cycloalcylène ou phénylène ;
    ou un sel pharmaceutiquement acceptable de celui-ci.
  2. Composé selon la revendication 1, dans lequel R1 est halogénoalkyle; R2 est hydrogène ; R3 est hydrogène ; R4 est hydrogène ; Ar1 est pyridindyile, pyrimidindyile, ou pyrazoldiyle ; X est O ou NR2 ; Y est une chaîne alcylène ou alcénylène contenant de 0 à 6 groupes sélectionnés dans le groupe constitué de O, NR3, C(O), C(O)O, C(O)NR4, OC(O)NR4, NR4C(O)NR4, NR4C(NR12)NR4, et Z, à condition que O, NR3, C(O), C(O)O, C(O)NR4, OC(O)NR4, NR4C(O)NR4, et NR4C(NR12)NR4 ne se lient pas directement l'un à l'autre, de sorte que le noyau A comprend de 14 à 36 éléments ; et où la chaîne alcylène ou alcénylène est substituée par 0 à 6 substituants alkyle ; et
    Z est C3-7cycloalcylène ou phénylène ;
    ou un sel pharmaceutiquenent acceptable de celui-ci.
  3. Composé selon la revendication 2, dans lequel R1 est trifluoroéthyle ou un sel pharmaceutiquement acceptable de celui-ci.
  4. Composé selon la revendication 2, dans lequel Ar1 est pyridindyile ou un sel pharmaceutiquement acceptable de celui-ci.
  5. Composé selon la revendication 2 dans lequel Ar1 est pyrimidindyile ou un sel pharmaceutiquement acceptable de celui-ci.
  6. Composé selon la revendication 2, dans lequel Ar1 est pyrazoldiyle ou un sel pharmaceutiquement acceptable de celui-ci.
  7. Composé selon la revendication 2, dans lequel X est O ou un sel pharmaceutiquement acceptable de celui-ci.
  8. Composé selon la revendication 2, dans lequel X est NR2 ou un sel pharmaceutiquement acceptable de celui-ci.
  9. Composition comprenant un composé selon l'une quelconque des revendications 1 à 8, ou un sel pharmaceutiquement acceptable de ceux-ci, et un support pharmaceutiquement acceptable.
  10. Composition selon la revendication 9, comprenant en outre au moins un composé supplémentaire ayant des bénéfices thérapeutiques pour le VHC, le composé étant sélectionné dans le groupe constitué des interférons, des cyclosporines, des interleukines, des inhibiteurs de la métalloprotéase du VHC, des inhibiteurs de la sérine protéase du VHC, des inhibiteurs de la polymérase du VHC, des inhibiteurs de l'hélicase du VHC, des inhibiteurs de la protéine NS4B du VHC, des inhibiteurs d'entrée du VHC, des inhibiteurs d'assemblage du VHC, des inhibiteurs de sortie du VHC, des inhibiteurs de la protéine NS5A du VHC, des inhibiteurs de la protéine NS5B du VHC, et des inhibiteurs du réplicon du VHC.
  11. Composé selon l'une quelconque des revendications 1 à 8 pour une utilisation dans une méthode de traitement d'une infection de l'hépatite C.
  12. Composé pour une utilisation selon la revendication 11, comprenant en outre l'administration d'au moins un composé supplémentaire ayant des bénéfices thérapeutiques pour le VHC, le composé étant sélectionné dans le groupe constitué des interférons, des cyclosporines, des interleukines, des inhibiteurs de la métalloprotéase du VHC, des inhibiteurs de la sérine protéase du VHC, des inhibiteurs de la polymérase du VHC, des inhibiteurs de l'hélicase du VHC, des inhibiteurs de la protéine NS4B du VHC, des inhibiteurs d'entrée du VHC, des inhibiteurs d'assemblage du VHC, des inhibiteurs de sortie du VHC, des inhibiteurs de la protéine NS5A du VHC, des inhibiteurs de la protéine NS5B du VHC, et des inhibiteurs du réplicon du VHC.
EP12715793.1A 2011-04-14 2012-04-09 Composés de triazine macrocycliques pour le traitement de l'hépatite c Not-in-force EP2697233B1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201161475484P 2011-04-14 2011-04-14
PCT/US2012/032674 WO2012154353A1 (fr) 2011-04-14 2012-04-09 Composés de triazine macrocycliques pour le traitement de l'hépatite c

Publications (2)

Publication Number Publication Date
EP2697233A1 EP2697233A1 (fr) 2014-02-19
EP2697233B1 true EP2697233B1 (fr) 2015-01-14

Family

ID=45992861

Family Applications (1)

Application Number Title Priority Date Filing Date
EP12715793.1A Not-in-force EP2697233B1 (fr) 2011-04-14 2012-04-09 Composés de triazine macrocycliques pour le traitement de l'hépatite c

Country Status (3)

Country Link
US (1) US8933066B2 (fr)
EP (1) EP2697233B1 (fr)
WO (1) WO2012154353A1 (fr)

Families Citing this family (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8629150B2 (en) 2011-09-28 2014-01-14 Bristol-Myers Squibb Company Compounds for the treatment of hepatitis C
US8697706B2 (en) 2011-10-14 2014-04-15 Bristol-Myers Squibb Company Compounds for the treatment of hepatitis C
US8916702B2 (en) 2012-02-06 2014-12-23 Bristol-Myers Squibb Company Compounds for the treatment of hepatitis C
WO2014062636A1 (fr) 2012-10-18 2014-04-24 Bristol-Myers Squibb Company Composés pour le traitement de l'hépatite c
JP2016507559A (ja) 2013-02-07 2016-03-10 ブリストル−マイヤーズ スクイブ カンパニーＢｒｉｓｔｏｌ−Ｍｙｅｒｓ Ｓｑｕｉｂｂ Ｃｏｍｐａｎｙ Ｈｃｖエントリー阻害剤としての大環状分子
WO2014123894A1 (fr) 2013-02-07 2014-08-14 Bristol-Myers Squibb Company Composés macrocycliques utilisés comme inhibiteurs de pénétration du vhc
CN105143233A (zh) 2013-03-07 2015-12-09 百时美施贵宝公司 用于治疗丙型肝炎的化合物
US9708324B2 (en) * 2015-02-05 2017-07-18 Merck Patent Gmbh Macrocyclic compounds as IRAK1/4 inhibitors and uses thereof

Family Cites Families (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS62126178A (ja) 1985-11-26 1987-06-08 Mitsubishi Petrochem Co Ltd 新規トリアジン誘導体及びこれを含む除草剤
KR100798579B1 (ko) 2001-03-31 2008-01-28 동화약품공업주식회사 신규의 메톡시-1,3,5-트리아진 유도체 및 그를 포함하는약학적 조성물
US7163943B2 (en) 2001-09-21 2007-01-16 Reddy Us Therapeutics, Inc. Methods and compositions of novel triazine compounds
US7169785B2 (en) 2001-09-21 2007-01-30 Reddy Us Therapeutics, Inc. Methods and compositions of novel triazine compounds
DE10239042A1 (de) 2002-08-21 2004-03-04 Schering Ag Makrozyclische Pyrimidine, deren Herstellung und Verwendung als Arzneimittel
KR100490893B1 (ko) 2002-10-11 2005-05-23 (주) 비엔씨바이오팜 2-메톡시-1,3,5-트리아진 유도체, 그 제조방법 및 이를 포함하는 항바이러스용 약학적 조성물
US20050014753A1 (en) 2003-04-04 2005-01-20 Irm Llc Novel compounds and compositions as protein kinase inhibitors
CA2667031C (fr) 2006-10-27 2013-01-22 Merck & Co., Inc. Inhibiteurs de protease ns3 du vhc
US20120009151A1 (en) 2007-12-21 2012-01-12 Progenics Pharmaceuticals, Inc. Triazines And Related Compounds Having Antiviral Activity, Compositions And Methods Thereof
CA2722326A1 (fr) 2008-04-24 2009-10-29 Incyte Corporation Composes macrocycliques et leur utilisation a titre d'inhibiteurs de kinase
US8044087B2 (en) 2008-09-29 2011-10-25 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
WO2010118367A2 (fr) 2009-04-10 2010-10-14 Progenics Pharmaceuticals, Inc. Pyrimidines antivirales
MX2012004032A (es) 2009-10-14 2012-05-08 Bristol Myers Squibb Co Compuestos para el tratamiento de hepatitis c.
US8445490B2 (en) 2009-10-14 2013-05-21 Bristol-Myers Squibb Company Compounds for the treatment of hepatitis C
EP2566872B1 (fr) 2010-05-04 2014-12-24 Bristol-Myers Squibb Company Composés destinés au traitement de l'hépatite c
US8765944B2 (en) 2010-08-19 2014-07-01 Bristol-Myers Squibb Company Compounds for the treatment of hepatitis C
US8629150B2 (en) 2011-09-28 2014-01-14 Bristol-Myers Squibb Company Compounds for the treatment of hepatitis C
US8697706B2 (en) 2011-10-14 2014-04-15 Bristol-Myers Squibb Company Compounds for the treatment of hepatitis C
US8916702B2 (en) 2012-02-06 2014-12-23 Bristol-Myers Squibb Company Compounds for the treatment of hepatitis C

Also Published As

Publication number Publication date
EP2697233A1 (fr) 2014-02-19
US20130095066A1 (en) 2013-04-18
US8933066B2 (en) 2015-01-13
WO2012154353A1 (fr) 2012-11-15

Similar Documents

Publication Publication Date Title
US8586584B2 (en) Compounds for the treatment of hepatitis C
EP2697233B1 (fr) Composés de triazine macrocycliques pour le traitement de l'hépatite c
EP2760872B1 (fr) Composés pour le traitement de l'hépatite c
US8697706B2 (en) Compounds for the treatment of hepatitis C
EP2948434B1 (fr) Dérivés squariques pour le traitement de l'hépatite c
EP2953954B1 (fr) Composés macrocycliques utilisés comme inhibiteurs de pénétration du vhc
US8987264B2 (en) 1,3,5-triazine derivatives of spiro bicyclic oxalamide-compounds for treatment of hepatitis C
US9745322B2 (en) Compounds for the treatment of hepatitis C
US9868743B2 (en) Macrocyclic molecules as HCV entry inhibitors
EP2964630B1 (fr) Composés de pyrimidine pour le traitement de l'hépatite c
US8987265B2 (en) Substituted 1,3,5-triazine derivatives of fused bicyclic oxalamide compounds for treatment of Hepatitis C
EP2948151B1 (fr) Dérivés d'ammonium pour le traitement de l'hépatite c
US9422311B2 (en) Compounds for the treatment of hepatitis C
EP2948445B1 (fr) Dérivés de guanidine pour le traitement de l'hépatite c

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20131024

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR

DAX Request for extension of the european patent (deleted)
GRAP Despatch of communication of intention to grant a patent

Free format text: ORIGINAL CODE: EPIDOSNIGR1

INTG Intention to grant announced

Effective date: 20140804

GRAS Grant fee paid

Free format text: ORIGINAL CODE: EPIDOSNIGR3

GRAA (expected) grant

Free format text: ORIGINAL CODE: 0009210

AK Designated contracting states

Kind code of ref document: B1

Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR

REG Reference to a national code

Ref country code: GB

Ref legal event code: FG4D

REG Reference to a national code

Ref country code: CH

Ref legal event code: EP

REG Reference to a national code

Ref country code: IE

Ref legal event code: FG4D

REG Reference to a national code

Ref country code: AT

Ref legal event code: REF

Ref document number: 706999

Country of ref document: AT

Kind code of ref document: T

Effective date: 20150215

REG Reference to a national code

Ref country code: DE

Ref legal event code: R096

Ref document number: 602012004941

Country of ref document: DE

Effective date: 20150305

REG Reference to a national code

Ref country code: NL

Ref legal event code: VDEP

Effective date: 20150114

REG Reference to a national code

Ref country code: AT

Ref legal event code: MK05

Ref document number: 706999

Country of ref document: AT

Kind code of ref document: T

Effective date: 20150114

REG Reference to a national code

Ref country code: LT

Ref legal event code: MG4D

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: FI

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20150114

Ref country code: LT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20150114

Ref country code: SE

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20150114

Ref country code: BG

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20150414

Ref country code: NO

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20150414

Ref country code: HR

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20150114

Ref country code: ES

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20150114

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: AT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20150114

Ref country code: NL

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20150114

Ref country code: IS

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20150514

Ref country code: LV

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20150114

Ref country code: PL

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20150114

Ref country code: RS

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20150114

Ref country code: GR

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20150415

REG Reference to a national code

Ref country code: DE

Ref legal event code: R097

Ref document number: 602012004941

Country of ref document: DE

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: CZ

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20150114

Ref country code: RO

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20150114

Ref country code: SK

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20150114

Ref country code: EE

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20150114

Ref country code: DK

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20150114

PLBE No opposition filed within time limit

Free format text: ORIGINAL CODE: 0009261

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: NO OPPOSITION FILED WITHIN TIME LIMIT

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: MC

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20150114

Ref country code: LU

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20150409

REG Reference to a national code

Ref country code: CH

Ref legal event code: PL

26N No opposition filed

Effective date: 20151015

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: IT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20150114

REG Reference to a national code

Ref country code: IE

Ref legal event code: MM4A

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: LI

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20150430

Ref country code: CH

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20150430

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: SI

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20150114

REG Reference to a national code

Ref country code: FR

Ref legal event code: PLFP

Year of fee payment: 5

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: IE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20150409

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: BE

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20150114

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: MT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20150114

REG Reference to a national code

Ref country code: FR

Ref legal event code: PLFP

Year of fee payment: 6

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: SM

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20150114

Ref country code: HU

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT; INVALID AB INITIO

Effective date: 20120409

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: CY

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20150114

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: PT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20150514

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: TR

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20150114

REG Reference to a national code

Ref country code: FR

Ref legal event code: PLFP

Year of fee payment: 7

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: GB

Payment date: 20180329

Year of fee payment: 7

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: FR

Payment date: 20180315

Year of fee payment: 7

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: MK

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20150114

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: DE

Payment date: 20180327

Year of fee payment: 7

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: AL

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20150114

REG Reference to a national code

Ref country code: DE

Ref legal event code: R119

Ref document number: 602012004941

Country of ref document: DE

GBPC Gb: european patent ceased through non-payment of renewal fee

Effective date: 20190409

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: GB

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20190409

Ref country code: DE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20191101

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: FR

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20190430